• Nenhum resultado encontrado

Association Between Insulin Resistance, Glucose Intolerance, and Hypertension in Pregnancy

N/A
N/A
Protected

Academic year: 2017

Share "Association Between Insulin Resistance, Glucose Intolerance, and Hypertension in Pregnancy"

Copied!
8
0
0

Texto

(1)

© Mary Ann Liebert, Inc. Pp. 53–59

DOI: 10.1089/met.2008.0043

Association Between Insulin Resistance, Glucose

Intolerance, and Hypertension in Pregnancy

Carlos Antonio Negrato, M.D., Ph.D.,

1

Lois Jovanovic, M.D., Ph.D.,

2

Marcos Antonio Tambascia, M.D., Ph.D.,

3

Bruno Geloneze, M.D., Ph.D.,

3

Adriano Dias, Ph.D.,

4

Iracema de Mattos Paranhos Calderon, Ph.D.,

5

and Marilza Vieira Cunha Rudge, Ph.D.

5

Abstract

There is an association between insulin resistance, glucose intolerance, and essential hypertension, but the

re-lation between insulin resistance, glucose intolerance, and hypertension diagnosed during pregnancy is not

well understood. Transient hypertension of pregnancy, the new-onset nonproteinuric hypertension of late

preg-nancy, is associated with a high risk of later essential hypertension and glucose intolerance; thus, these

condi-tions may have a similar pathophysiology. To assess the association between insulin resistance, glucose

intol-erance, essential hypertension, and subsequent development of proteinuric and nonproteinuric hypertension

in pregnancy in women without underlying essential hypertension , we performed a prospective study

com-paring glucose (fasting, 1 and 2 hours postglucose load), insulin, glycosylated hemoglobin (HbA1c),

high-den-sity lipoprotein cholesterol (HDL-C), and triglycerides levels on routine screening for gestational diabetes

mel-litus. Women who developed hypertension in pregnancy (

n

37) had higher glycemic levels (fasting, 1 and 2

hours postglucose load) on a 100-gram oral glucose loading test, although only the fasting values showed a

statistical significance (

p

0.05), and a significantly higher frequency of abnormal glucose loading tests, two

hours after glucose load (

140 mg/dL) (

p

0.05) than women who remained normotensive (

n

180). Glucose

intolerance was common in women who developed both subtypes of hypertension, particularly preeclampsia.

Women who developed hypertension had greater prepregnancy body mass index (

p

0.0001), higher frequency

and intensity of acanthosis nigricans (

p

0.0001), and higher baseline systolic and diastolic blood pressures (

p

0.0001 for both), although all subjects were normotensive at baseline by study design; they also presented

lower levels of HDL-C (

p

0.05). However, after adjustment for these and other potential confounders, an

ab-normal glucose loading test remained a significant predictor of development of hypertension (

p

0.05) and,

specifically, preeclampsia (

p

0.01). There was a trend toward higher insulin and homeostasis model

assess-ment–insulin resistance (HOMA-IR) levels in women developing any type of hypertension. When comparing

women that remained normotensive to term with those with transient hypertension and preeclampsia, the

preeclamptic women were born with lower weight (

p

0.05) and shorter length (

p

0.005); at screening they

were older (

p

0.005), showed higher frequency and intensity of acanthosis nigricans (

p

0.0001), had higher

prepregnancy BMI (

p

0.0005), as well as higher baseline systolic and diastolic blood pressures (

p

0.0001 for

both). They also showed higher HOMA-IR levels that did not show a statistical significance. When glucose

tol-erance status was taken in account, an association was found between increasing indexes of hypertension (

p

0.05) and of HOMA-IR (

p

0.05) with the worsening of glucose tolerance. These results suggest that insulin

resistance and relative glucose intolerance are associated with an increased risk of new-onset hypertension in

pregnancy, particularly preeclampsia, and support the hypothesis that insulin resistance may play a role in the

pathogenesis of this disorder.

53

1Research Support Center, Bauru’s Diabetics Association, Bauru, São Paulo, Brazil. 2Sansum Diabetes Research Institute, Santa Barbara, California.

3Department of Endocrinology and Diabetes , University of Campinas–UNICAMP, Bauru, São Paolo, Brazil.

(2)

Introduction

H

YPERTENSION, A COMMON DISORDER complicating

preg-nancy (6–9%), remains a leading cause of maternal mor-tality (around 15%) in the United States1and worldwide.2

Hypertension is associated with glucose intolerance and in-sulin resistance.3,4Increased insulin resistance found in

nor-motensive offspring of hypertensive parents5,6suggests that

insulin resistance may precede the development of essential hypertension and may also cause it. Possible mechanisms by which insulin resistance or hyperinsulinemia may predis-pose to hypertension include increased renal sodium reab-sorption,7 activation of sympathetic nervous system

activ-ity,8and stimulation of cell membrane cation transport.9

Several investigators have reported insulin as a regulator of blood pressure during pregnancy, and they associated plasma insulin levels with hypertension.10The role of insulin

resistance in the pathogenesis of hypertension arising for the first time in pregnancy is still not well understood.11

Preg-nancy is a state of increased insulin resistance12,13;

hyper-tension in pregnancy generally presents in the third trimester when insulin resistance that normally occurs in pregnancy is higher.14,15Some conditions that are associated with

in-sulin resistance, like obesity16and gestational diabetes,17–19

may be risk factors for the occurrence of hypertension in pregnancy. A role for insulin resistance in cases of new-on-set hypertension in pregnancy is also suggested by the as-sociation of transient hypertension, or new-onset nonpro-teinuric hypertension of late pregnancy, with a high incidence of later essential hypertension.20,21

This study was performed to assess whether insulin re-sistance and glucose intolerance are associated with an in-creased risk of hypertension in pregnancy among women without essential hypertension, but with several degrees of glucose tolerance at the time of routine screening for gesta-tional diabetes mellitus. Some of these women subsequently developed hypertension and some remained normotensive to term.

Methods

Subjects

The study population consisted of 217 women with sin-gleton pregnancies, assigned to participate when the screen-ing for gestational diabetes was performed in the third trimester, between 24 and 28 weeks of gestation, if they pre-sented no previous or current history of hypertension. Two tests were performed to detect any degree of glucose intol-erance: a 100-gram oral glucose tolerance test (OGTT) and a glycemic profile. The cutoff values for the OGTT were those proposed by Carpenter and Coustan (fasting ⱖ95 mg/dL; 1 hour ⱖ180 mg/dL; 2 hours ⱖ155 mg/dL; 3 hours ⱖ140 mg/dL)22and for the glycemic profile those proposed by

Gillmer (fasting ⱖ90 mg/dL and/or 1–2 hours postprandial

ⱖ130 mg/dL.23The glycemic profile was done within a week

after the OGTT. Patients were taught how to measure their glycemic levels using a glucose reflectance meter in the fast-ing state at 8 a.m., then postprandially at 10 a.m., midday, and at 2, 4, and 6 p.m. If the results were borderline (10 mg/dL higher or lower than the cutoff values), tests were repeated. After these procedures they were classified into four groups: (1) group IA, normal OGTT and glycemic

pro-file (normoglycemic or control group; (2) group IB, normal OGTT and abnormal glycemic profile (mild hyperglycemic group); (3) group IIA, abnormal OGTT and normal glycemic profile (gestational diabetes group); (4) group IIB, abnormal OGTT and glycemic profile (overt gestational diabetes group).

Among the women enrolled in the study, 37 presented with new-onset hypertension in index pregnancy and 180 re-mained normotensive to term. New-onset hypertension in pregnancy was defined as a systolic blood pressure (SBP) of 140 mmHg or greater or diastolic blood pressure (DBP) of 90 mmHg or greater, constituting a rise in SBP of 30 mmHg or greater or in diastolic blood pressure of 15 mmHg or greater over first-trimester values measured on at least two occasions more than 6 hours apart and developing after 24 weeks of gestation in a previously normotensive woman.24

Eighteen of the hypertensive women had transient hyper-tension, defined as hypertension without significant pro-teinuria (24-hour urinary protein ⬍300 mg); 19 women had preeclampsia, defined as hypertension in association with 24-hour urinary protein of 300 mg or greater. The nor-motensive control group included women who did not de-velop hypertension during pregnancy or in the immediate postpartum period.

To avoid inclusion of essential hypertensive women in the study, we excluded those women for which we were unable to document a normal blood pressure reading in the first trimester, or, if this was unavailable, in the 6 months pre-ceding pregnancy or at a 6-week postpartum visit. Women were also excluded if they had any underlying medical ill-ness, such as renal or liver disease, connective tissue disease, or diabetes antedating pregnancy, or were taking any med-ications that could affect glucose tolerance or blood pressure. This study was approved by the Institutional Review Board of the School of Medicine of Botucatu–São Paulo State Uni-versity–UNESP, Brazil.

Data collection

Maternal characteristics, such as age, parity, ethnicity, weight and length at birth, and weight and body mass in-dex (BMI) prepregnancy, were obtained. At screening, weight, height, blood pressure, waist and hip circumference, and hip circumference were measured. Obesity was defined as a prepregnancy BMI ⱖ30 kg/m2.

Blood samples were collected at the time the OGTT was done to determine fasting one and 2-hour postglucose load lev-els of glycemia, glycosylated hemoglobin (HbA1c), high-den-sity lipoprotein cholesterol (HDL-C), triglycerides, and insulin. Blood pressure was routinely measured in all patients.

(3)

The homeostasis model assessment (HOMA-IR)was cal-culated to determine the degree of insulin resistance and the secretory capacity of cells, according to following equa-tions, proposed by Mattews et al.25: HOMA-IRglycemia

(mMol/L)⫻insulin (U/mL)/22.5. Reference value⫽1.66⫾

0.79; men⫽1.69⫾0.72; women⫽1.65⫾0.81; insulin re-sistanceⱖ2.71.26 HOMA-insulin (U/mL)/glycemia

(mMol/L)⫺3.5. Reference value⫽200–250.

Statistical analysis

Means, standard deviations, and percentages were pre-sented. Continuous data were compared among three (nor-motensive, transitory hypertension, and preeclampsia) or four (IA, IB, IIA, and IIB) groups using the analysis of vari-ance (one-way, ANOVA) with Tukey posttest comparisons. Posttest for linear trend between column mean and column number was also used in some analyses. When necessary, an unpaired Student t-test or corrected Student t-test–Welch was used to compare two groups (normotensive vs. hyper-tensive). Discrete data among three (normotensive, transi-tory hypertension, and preeclampsia) or four (IA, IB, IIA, and IIB) groups were analyzed using the chi-squared test. When necessary, the Fisher exact test was used to compare the two conditions (normotensive vs. hypertensive). To de-tect possible correlations between independent and depen-dent or between two dependepen-dent variables, linear regression

was applied and considered significant when r⬎0.7. A p

value ⬍0.05 was considered statistically significant.

Results

Women who developed hypertension in pregnancy showed a greater prepregnancy BMI (31.05 versus 26.22 ) and higher frequency and intensity of acanthosis nigricans (77.7% versus 49.1%) (p ⱕ 0.001 for both) than those who remained nor-motensive; and although all groups had normal blood pressure at baseline as required by study entry criteria, women who de-veloped hypertension had significantly higher baseline SBP (129.50 mmHg versus 115.10 mmHg) and DBP (83.80 mmHg versus 75.10 mmHg) than women remaining normotensive to term (pⱕ0.001 for both). Their SBP (126.20 mmHg versus 109.80 mmHg) and DBP (85.40 mmHg versus 72.40 mmHg) were also higher at 24–28 weeks of gestation when the screening was per-formed, than women remaining normotensive to term (p

0.001 for both).They also showed higher fasting glucose (99.83 mg/dL vs. 88.86 mg/dL) and lower HDL-C levels (56.09 mg/dL vs. 63.15 mg/dL) (p⬍0.05 for both). They also pre-sented higher levels of glucose intolerance (p⬍0.05); had lower birth weight, shorter birth length, were older, more frequently multiparas, had higher waist-to-hip ratio, higher levels of glycemia 1 and 2 hours postglucose load at OGTT, and higher levels of HbA1c and triglycerides, although not statistically sig-nificant (Table 1).

TABLE1. DEMOGRAPHIC ANDCLINICALVARIABLES INWOMENREMAININGNORMOTENSIVE TOTERM ANDWOMENDEVELOPINGHYPERTENSION INPREGNANCY

Normotensive Hypertension in pregnancy

(n⫽180) (n⫽37) p value

Maternal birth weight (grams) 3274.38 (⫾627.01) 3005.38 (⫾816.17) 0.057 Maternal birth length (cm) 48.19 (⫾2.77) 47.00 (⫾3.67) 0.058 Age (years) 30.58 (⫾5.93) 31.97 (⫾5.31) 0.189 Height (meters) 1.63 (⫾0.06) 1.63 (⫾0.06) 0.999

Race (% Caucasian) 66.1 75.7 0.267

First pregnancy (%) 31.1 27.0 0.279

Gestational age at OGTT 26.84 (⫾4.05) 26.48 (⫾3.90) 0.647 (weeks)

Pregravid BMI (kg/m2) 26.22 (6.66) 31.05 (6.92)a 0.0001a

Weight gain (kg) 11.10 (⫾6.5) 11.50 (⫾6.40) 0.735 Pregravid waist/hip ratio 0.82 (⫾0.08) 0.84 (⫾0.09) 0.482

Acanthosis (%) 49.1 77.7a 0.0001

BP at baseline (mmHg)

Systolic 115.10 (⫾17.60) 129.50 (⫾27.80)a 0.001a

Diastolic 75.10 (⫾10.80) 83.80 (⫾13.20)a 0.001a

BP at week 24 (mmHg)

Systolic 109.80 (⫾11.30) 126.20 (⫾14.20)a 0.0001a

Diastolic 72.40 (⫾8.40) 85.40 (⫾11.70)a 0.0001a

Fasting glucose at OGTT 88.86 (⫾29.15) 99.83 (⫾27.13)a 0.021a

(mg/dL)

1 hour postload at OGTT 158.10 (⫾59.30) 174.03 (⫾57.40) 0.164 (mg/dL)

2 hours postload at OGTT 137.81 (⫾54.16) 148.03 (⫾61.96) 0.342 (mg/dL)

HbA1c (%) 5.40 (⫾1.14) 5.74 (⫾1.24) 0.167 HDL-C (mg/dL) 63.15 (⫾17.26) 56.09 (⫾16.51)a 0.030a

Triglycerides (mg/dL) 199.58 (⫾89.81) 228.85 (⫾99.55) 0.092

aStatistically significant.

(4)

Those who developed transient hypertension in preg-nancy, compared with those remaining normotensive to term, showed a greater prepregnancy BMI (31.05 vs. 26.22), higher frequency and intensity of acanthosis nigricans (77.7% vs. 49.1%) (P ⱕ 0.001 for both), and higher baseline SBP (123.90 mmHg versus 115.10 mmHg) and DBP (80.60 mmHg versus 75.10 mmHg) (pⱕ0.001 for both). Their blood pres-sure, both systolic and diastolic, was also higher at screen-ing (122.80 mmHg vs. 109.80 mmHg) and (85.00 mmHg vs. 72.40 mmHg), respectively, than the normotensive group. They also showed higher fasting glucose (94.59 mg/dL vs. 88.86 mg/dL) and lower HDL-C levels (50.59 mg/dLvs. 63.15 mg/dL) (p⬍0.05 for both). They were younger, had shorter stature, were more frequently multiparas, had greater weight gain, higher waist-to-hip ratio, higher 1-hour and lower 2-hour levels of glucose postload, and higher lev-els of HbA1c and triglycerides that were not statistically sig-nificant.

Patients that developed preeclampsia, when compared with those that remained normotensive, were born with a lower weight (2723.85 g vs. 3274.38 g) (p⬍0. 0.05), shorter length (45.38 cm vs. 48.19 cm) (p⬍0.005), were older (34.87 years vs. 30.58 years) (p⬍0.005), had greater prepregnancy BMI (31.43 vs. 26.22) and higher frequency and intensity of

acanthosis nigricans (77.7% vs. 49.1%) (p⬍0.001 for both), higher baseline SBP (134.70 mmHg vs. 115.10 mmHg) and DBP (86.80 mmHg versus 75.10 mmHg) (pⱕ0.001 for both). Their blood pressure, both systolic and diastolic, was also higher at screening: SBP (129.50 mmHg vs. 109.80 mmHg) and DBP (85.80 mmHg vs. 72.40 mmHg), respectively (p

0.001 for both). They also showed higher fasting glucose lev-els (105.06 mg/dL versus 88.86 mg/dL) than the normoten-sive group (p– 0.05 for both). They were taller, had higher parity, greater weight gain, higher waist-to-hip ratio, higher levels of glycemia 1 hour and 2 hours postglucose load, and higher levels of HbA1c and triglycerides that also showed no statistical significance (Table 2).

Insulin levels measured at the time OGTT was performed tended to be higher among women who developed hyper-tension in pregnancy (16.25 U/mL) than among those who remained normotensive (12.80 U/mL), although without sta-tistical significance; but HOMA-IR levels (3.55 vs. 2.40) showed statistical significance between the two groups (p

0.05) (Table 3). When the hypertensive groups were analyzed separately, the group with preeclampsia presented the high-est insulin levels, followed by the transient hypertension and the normotensive groups (16.80 U/mL vs. 15.70 U/mL vs. 12.80 U/mL), respectively; also the highest levels of

HOMA-TABLE2. DEMOGRAPHIC ANDCLINICALVARIABLES INWOMENREMAININGNORMOTENSIVE TOTERM ANDWOMEN

DEVELOPING NEW-ONSETHYPERTENSION INPREGNANCY(TRANSIENTHYPERTENSION ORPREECLAMPSIA) Transient

Normotensive hypertension Preeclampsia

(n⫽180) (n⫽18) (n⫽19) p value

Maternal birth weight 3274.38 (⫾627.01) 3286.92 (⫾846.20) 2723.85 (⫾707.09)a 0.015a

(grams)

Maternal birth length 48.19 (⫾2.77) 48.62 (⫾2.40) 45.38 (⫾4.07)a 0.003a

(cm)

Age (years) 30.58 (⫾5.93) 28.91 (⫾5.44) 34.87 (⫾3.20)a 0.003a

Height (meters) 1.63 (⫾0.06) 1.61 (⫾0.06) 1.64 (⫾0.06) 0.185 Race (% Caucasian) 66.1 72.2 78.9 0.120 First pregnancy (%) 31.1 27.8 26.3 0.073 Gestational age at 26.84 (⫾4.05) 26.44 (⫾3.83) 26.53 (⫾4.08) 0.899

OGTT (weeks)

Pregravid BMI (kg/m2) 26.22 (6.66) 31.05 (6.92)a 31.43 (6.66)a 0.001a

Weight gain (kg) 11.10 (⫾6.5) 11.70 (⫾7.90) 11.40 (⫾6.38) 0,466 Pregravid waist/hip ratio 082 (⫾0.08) 0.83 (⫾0.12) 0.85 (⫾0.08) 0.733 Acanthosis (%) 49.1 77.7a 77.7a 0.0001

BP at baseline (mmHg)

Systolic 115.10 (⫾17.60) 123.90 (⫾25.70)a 134.70 (29.30)a 0.001a

Diastolic 75.10 (⫾10.80) 80.60 (⫾12.60)a 86.80 (13.30)a 0.001a

BP at week 24 (mmHg)

Systolic 109.80 (⫾11.30) 122.80 (⫾13.60)a 129.50 (14.30)a 0.001a

Diastolic 72.40 (⫾8.40) 85.00 (⫾11.50)a 85.80 (12.10)a 0.001a

Fasting glucose at 88.86 (⫾29.15) 94.59 (⫾27.76)a 105.06 (26.30)a 0.041a

OGTT (mg/dL)

1 hour postload at OGTT 158.10 (⫾59.30) 162.10 (⫾50.20) 185.90 (⫾63.10) 0.199 (mg/dL)

2 hours postload at 137.81 (⫾54.16) 128.56 (⫾51.75) 167.50 (⫾66.70) 0.088 OGTT (mg/dL)

HbA1c (%) 5.40 (⫾1.14) 5.61 (⫾1.38) 5.85 (⫾1.13) 0.238 HDL-C (mg/dL) 63.15 (⫾17.26) 50.59 (⫾17.28)a 60.98 (14.56) 0.020a

Triglycerides (mg/dL) 199.58 (⫾89.81) 234.78 (⫾71.80) 223.58 (⫾120.94) 0.227

aStatistically significant.

(5)

IR were found in the preeclampsia group followed by the transient hypertension and the normotensive groups (3.90 vs. 3.20 vs. 2.40), respectively, without statistical significance (Table 4).

Taking in account two diagnostic methods, the 100-gram OGTT and the glycemic profile to determine glucose toler-ance status, women that presented new-onset hypertension in pregnancy belonged significantly to the more glucose-in-tolerant groups when compared to the normotensive women (7.55%, IA; 13.79%, IB; 22.00%, IIA; and 23.26%, IIB; vs. 92.45%, IA; 86.21%, IB; 78.00%, IIA; 76.74%, IIB), respectively (p ⬍⬍ 0.05). The same trend was observed when patients were analyzed by subtypes of hypertension; transient hy-pertension was more frequently found in the group pre-senting mild gestational hyperglycemia (IB) and preeclamp-sia in the gestational diabetes (IIA) (p⬍0.05)(Table 4).

No absolute fasting glucose level distinguished reliably between women developing new-onset hypertension in pregnancy and normotensive women. Still, a significantly higher percentage of women who developed hypertension (43.24%) than remained normotensive (27.80%) had OGTT glucose levels of 140 mg/dL or greater, 2 hours after glucose load (p⬍0.05); particularly women developing preeclamp-sia (57.89%) had glucose levels in this range (p⬍0.05)

Using a muitivariate analysis to assess the risk for new-onset hypertension in pregnancy associated with an OGTT glucose level of 140 mg/dL or greater, 1 or 2 hours after glucose load, and after adjustment for maternal age, race (Caucasian versus non-Caucasian), and gestational age at OGTT, high glucose levels both in fasting, 1 hour and 2

hours postglucose load were associated with a significantly increased risk of hypertension (p⬍0.05).

Discussion

Insulin resistance is associated with and may be causal in essential hypertension.4,5,7–9The results of the present study

indicate a strong association between glucose intolerance, in-sulin resistance, and subsequent development of hyperten-sion in pregnancy, particularly the preeclampsia subtype. Glucose tolerance was evaluated before the development of hypertension, and it was found that relative glucose intoler-ance may precede the onset of this disorder. Women with insulin-dependent diabetes antedating pregnancy are known to have an increased risk of hypertension in pregnancy,27but

these women primarily have insulin deficiency rather than insulin resistance, and they often have renal dysfunction that might underlie blood pressure elevation. More recently, risk of hypertension in pregnancy has been reported by some,18,28–31 although not all32,33 investigators to be

in-creased among women with gestational diabetes, a disorder associated with underlying insulin resistance.34 Some,31,35

but not other,18studies have suggested a relation between

less-striking degrees of glucose intolerance and subsequent hypertension in pregnancy.

The present study carefully excluded preexisting essential hypertension by documentation of normal blood pressures before, early in pregnancy, and after the pregnant state. Al-though not uncommon during the reproductive years, es-sential hypertension is often undiagnosed in this population; TABLE 3. GLUCOSETOLERANCESTATUSVARIABLES INWOMENREMAININGNORMOTENSIVE

TOTERM AND WOMENDEVELOPING HYPERTENSION INPREGNANCY

Normotensive Hypertension pvalue

Insulin (U/mL) 12.80 (⫾10.90) 16.25 (⫾9.75)a 0.309

HOMA-IR 2.40 (⫾1.80) 3.55 (⫾1.95)a 0.036a

Glucose tolerance status (%) 0.044a

Group IA (n⫽53) 92.45 7.55 Group IB (n⫽57) 86.21 13.79 Group IIA (n⫽20) 78.00 22.00 Group IIB (n⫽86) 76.74 23.26

aStatistically significant.

Note:HOMA-IR, Homeostasis model assessment–insulin resistance.

TABLE 4. GLUCOSETOLERANCESTATUSVARIABLES INWOMENREMAININGNORMOTENSIVE TOTERM ANDWOMEN

DEVELOPINGNEW-ONSETHYPERTENSION INPREGNANCY(TRANSIENTHYPERTENSION ORPREECLAMPSIA) Transient

Normotensive hypertension Preeclampsia pvalue

Insulin (U/mL) 12.80 (⫾10.90) 15.70 (⫾10.00) 16.80 (⫾9.47) 0.077a

HOMA-IR 2.40 (⫾1.80) 3.20 (⫾2.10) 3.90 (⫾1.90) 0.090a

Glucose tolerance status (%) 0.048a

Group IA (n⫽53) 92.45 5.66 1.89 Group IB (n⫽57) 86.21 10.28 3.51 Group IIA (n⫽20) 78.00 5.00 17.00 Group IIB (n⫽86) 76.74 9.30 13.96

aStatistically significant.

(6)

many women do not routinely see a physician before preg-nancy, and they may not receive obstetric care until the sec-ond trimester of pregnancy, when there is a normal physio-logical decrease in blood pressure. Confirmation of previous or subsequent normotension among women diagnosed with hypertension in pregnancy in the present study eliminates the possibility that the glucose intolerance noted in these women could be explained by misclassification of women with preexisting essential hypertension. We also distin-guished between subtypes of hypertension in pregnancy and observed a significantly higher frequency of glucose intoler-ance (abnormal OGTTs) among women who developed any type of hypertension. The increased incidence of later es-sential hypertension reported among women with transient hypertension and preeclampsia36is consistent with this

ob-servation.

Significant associations were also found between new-on-set hypertension in pregnancy and prepregnancy BMI and blood pressures earlier in pregnancy. These observations are consistent with previously reported associations between hypertension in pregnancy and obesity,15,37 and excessive

pregnancy weight gain16and blood pressure in the second

trimester or earlier.38The greater BMIs noted among women

who are subsequently diagnosed with preeclampsia may re-flect early evidence of the edema characteristic of this disor-der or, alternatively, could be pathogenic.

The observation of higher first-trimester blood pressures in initially normotensive women who subsequently develop transient hypertension suggests an underlying tendency to high blood pressure in these women that is unmasked or ex-aggerated by pregnancy. Underlying essential hypertension is considered a risk factor for development of preeclamp-sia21,24; our observation of higher baseline blood pressures

among women developing this disorder indicates that rela-tive increases in blood pressure within the normal range are also associated with increased risk of developing the disease. The relation between glucose tolerance and subsequent development of hypertension in pregnancy remained sig-nificant in our population after adjustment for maternal age, race, gestational age at OGTT, and prepregnancy BMI. The trend toward higher insulin levels in women who developed hypertension in pregnancy, although not statistically signif-icant, nevertheless suggests a role for insulin resistance or hyperinsulinemia in the pathogenesis of this disorder. A link between insulin resistance and development of hypertension in pregnancy is also supported by the association of hyper-tension in pregnancy with increased BMI in this and other studies.15,21,24

The finding of an association between mild degrees of perglycemia (group IB) and higher incidence of transient hy-pertension suggest that even slightly higher levels of insulin are associated with an increased risk for developing these conditions.31Some investigators consider primigravidity to

be a criterion for the diagnosis of preeclampsia36; however,

primigravidas (27.03%) in our study were less frequently di-agnosed with transient hypertension and preeclampsia than multigravidas (72.97%).

In summary, our results indicate that glucose intolerance may be an important predictor of the development of new-onset hypertension in pregnancy. These data provide support for the hypothesis that insulin resistance may have a role in the pathogenesis of hypertension in pregnancy.

Acknowledgments

We thank Professor Alex Rafacho and Professor José Roberto Bosqueiro for helping in the statistical analyses and in computing data.

References

1. Diagnosis and management of preeclampsia and eclampsia. ACOG practice bulletin no.33: American College of Obste-tricians and Gynecologists. Obstet Gynecol2002;99:159–167. 2. Villar J, Say L, Shennan A, Lindheimer M, Duley L, Conde-Agudelo A, Merialdi M. Methodological and techinical is-sues related to the diagnosis, screening, prevention and treatment of preeclampsia and eclampsia. Int J Gynaecol Ob-stet2004;85(Suppl.1):S28–S41.

3. Reaven GM. Banting lecture 1988: Role of insulin resistance in human disease. Diabetes1988;37:1595–1607.

4. Ferrannini E, Buzzigoli G, Bonnadonna R, Giorico MA, Oleg-gini M, Graziadei L,Pedrinelli R, Brandi L. Bevilacqua S. In-sulin resistance in essential hypertension. N Engl J Med 1987;317:350–357.

5. Beatty OL, Harper R, Sheridan B, Atkinson AB. Insulin re-sistance in offspring of hypertensive parents. Br Med J 1993;307:92–96.

6. Dabelea D, Pettit D. Long-term implications: child and adult. In Hod M, Jovanovic L, Di Renzo GC,Leiva A, Langer O, eds. Textbook of Diabetes and Pregnancy. London: Martin Dunitz; 2003: 628 pp.

7. DeFronzo RA, Cooke C, Andres R, Faloona GR, Davis PJ. The effect of insulin in renal handling of sodium, calcium, potassium, and phosphate in man. J Clin Invest 1975;55: 845–855.

8. Rowe JW, Young JB, Minaker KL. Stevens AL, Pallotta J, Landsberg L. Effect of insulin and glucose infusions on sym-pathetic nervous system activity in normal man. Diabetes 1981;30:219–225.

9. Doria A, Fioretto P, Avogaro A. Carraro A, Morocutti A, Trevisan R, Frigato F, Crepaldi G, Viberti O, Nosadini R. In-sulin resistance is associated with high sodium-lithium countertransport in essential hypertension. Aro J Physiol 1991;261:E684–E691.

10. Hamasaki T, Yasuhi I, Masuki H, Ishimaru T. Hyperinsu-linemia increases the risk of gestational hypertension. Int J Gynecol Obstet1996;55:141–145.

11. Bryson CL, Ioannou GN, Rulyak SJ, Critchlow C. Associa-tion between gestaAssocia-tional diabetes and pregnancy-induced hypertension. Am J Epidemiol2003;158:1148–1153.

12. Rodie VA, Freeman DJ, Sattar N, Greer IA. Pre-eclampsia and cardiovascular disease: metabolic syndrome of preg-nancy? Atherosclerosis2004;175:189–202.

13. Parretti E, Lapolla A, Dalfrà M, Pacini G, Mari A, Cioni R, Marzari C, Scarselli G, Mello G. Preeclampsia in lean nor-motensive normotolerant pregnant women can be predicted by simple insulin sensitivity indexes. Hypertension 2006;47 449–453.

14. Di Cianni G, Miccoli R, Volpe L, Lencioni C, Del Prato S. In-termediate metabolism in normal pregnancy and in gesta-tional diabetes. Diabetes Metab Res Rev2003;19:259–270. 15. Eskenazi B, Fenster L, Sidney S. A multivariate analysis of

risk factors for pre-eclampsia. JAMA1991;266:237–241. 16. Langer O, Yogev Y, Xenakis E M J, Brustman L. Overweight

and obese in gestational diabetes: The impact of pregnancy outcome. Am J Obstet Gynecol2005;192:1768–1776.

(7)

18. Suhonen L, Teramo K. Hypertension and pre-eclampsia in women with gestational glucose intolerance. Acta Obstei Gy-necol Scand1993;72:269–272.

19. Moore T. Diabetes in pregnancy. In Maternal-fetal Medicine: Principles and Pratice, 5th ed. Creasy RK, Resnik R, Iams JD, eds. Philadelphia: Saunders; 2004: 1023–1061.

20. Pouta A, Hartikainen A, Sovio U, Gissler M, Laitinen J, Mc-Carthy MI, Roukonen A, Elliot P, Järvelin M. Manifestations of metabolic syndrome after hypertensive pregnancy. Hy-pertension2004;43:825–831.

21. Sattar N, Greer IA. Pregnancy complications and maternal cardiovascular risk:opportunities for intervention and screening? Br Med J2002;325:157–160.

22. Carpenter MW, Coustan DR. Criteria for screening test for gestational diabetes. Am J Obstet Gynecol1982;144:768–773. 23. Gillmer MDG, Beard RW, Brooke FM, Oakley NW. Carbo-hydrate metabolism in pregnancy. Br Med J1975;3:399–404. 24. Solomon CG, Graves SW, Greene MF, Seely EW.Glucose in-tolerance as a predictor of hypertension in pregnancy. Hy-pertension1994;23:717–721.

25. Mathews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: Insulin re-sistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28: 412–419.

26. Geloneze B, Repetto EM, Geloneze SR et al. The threshold value for insulin resistance HOMA-IR) in an admixtured population. IR in the Brazilian Metabolic Syndrome Study. Diab Res Clin Pract2005;72:219–220.

27. Greene MF, Hare JW, Krache M, Philippe M, Barss VA, Saltz-man DH, Nadel A, Younger MD, Schenl JE. Prematurity among insulin-requiring diabetic gravid women. Aro J Ob-stei Gynecol1989;161:106–111.

28. Aberg A, Rydhstroem H, Frid A. Impaired glucose tolerance associated with adverse pregnant outcome: a population based study in southern sweden. Am J Obstet Gynecol2001; 184:77–83.

29. Davey DA, I Mac Gyllivray. The classification and a defini-tion of the hypertensive disorders of pregnancy. Am J Ob-stet Gynecol1984;158:892.

30. Montoro MN, Kjos SL, Chandler M, Peters RK, Xiang AH, Buchanan TA. Insulin resistance and preeclampsia in gesta-tional diabetes mellitus. Diabetes Care2005;28:1995–2000. 31. Negrato C A, Jovanovic L, Tambascia MA, Calderon ID,

Geloneze B, Dias A, Rudge MV. Mild gestational hypergly-caemia as risk factor for metabolic syndrome in pregnancy and adverse perinatal outcomes. Diabetes Metab Res Rev 2008;24(4):324–330.

32. Jacobson JD, Cousins L. A population-based study of ma-ternal and perinatal outcome in patients with gestational di-abetes. A,n J Obstei Gynecol1989;161:981–986.

33. Magee MS, Walden CE, Benedetti TJ. Knopp RH. Influence of diagnostic criteria on the incidence of gestational diabetes and perinatal morbidity. lAMA1993;269:609–615.

34. Ward WK, Johnston CLW, Beard JC. Benedetti TJ, Halter JB, Porte D. Insulin resistance and impaired insulin secretion in subjects with histories of gestationai diabetes mellitus. Dia-betes1985;34:861–869.

35. Bo Simona, Menato G, Gallo M-L et al: Mild gestational hy-perglycemia, the metabolic syndrome and adverse neonatal outcomes. Acta Obstet GynecolScand 2004;83:335–340. 36. Fisher KA, Luger A, Spargo BH, Lindheimer MD.

Hyper-tension in pregnancy: clinical pathological correlations and remote prognosis. Medicine. 1981;60:267–276.

37. Scheafer-Graf UM, Hever R, Kilavuz O, Pandura A, Henrich W, Vetter K. Maternal obesity not maternal glucose values correlates best with high rates of fetal macrosomia in preg-nancies complicated by gestational diabetes. J Perinat Med. 2002;30:313–21.

38. Lucas MJ: Diabetes complicating pregnancy. Obstet Gynecol Clin North Am2001;28:513–536.

Address reprint requests to:

Carlos Antonio Negrato, M.D., Ph.D. Research Support Center Bauru’s Diabetics Association Rua Saint Martin 27–07 Bauru, São Paulo, Brazil 17043–081

(8)

1. Giuseppe Maria Maruotti, Laura Sarno, Raffaele Napolitano, Laura Letizia Mazzarelli, Filomena Quaglia, Angela Capone, Alfredo

Capuano, Pasquale Martinelli. 2012. Preeclampsia in women with chronic kidney disease.

Journal of Maturnal-Futal and Nuonatal

Mudicinu

25

:8, 1367-1369. [

CrossRef

]

Referências

Documentos relacionados

Insulin sensitivity and glycemia were assessed using an oral glucose tolerance test (OGTT) and the homeostasis model assessment of insulin resistance (HOMA-IR index) evaluation after

Regarding pregnancy complications, 1 of the hypertensive women developed malignant hypertension (with fetal growth restriction and preterm delivery at 29 weeks), 2 had acute

possibilidades da educação superior a distância, apoiada na utilização intensiva das tecnologias de informação e comunicação TICs, no contexto das novas políticas públicas

The main changes in Vitamin D Deficiency group were: (a) higher levels of triglyceride, VLDL-C, insulin, glucose, HbA1c, BMI, percentage of body fat, percentage of lean mass, waist

Objective : to evaluate the association between levels of serum uric acid (UA) and the following laboratory proile: fasting glucose ≥ 100 mg/dl, triglycerides ≥ 150 mg/dl and

The present study is in accordance with these findings, as fetuin-A levels decreased significantly as the fasting glucose levels and insulin resistance decreased after

Natural history of glucose tolerance, beta-cell function and peripheral insulin sensitivity in cystic fibrosis patients with fasting euglycemia. Glucose intolerance in cystic

A case of a patient with AS hemoglobinopathy who developed proliferative sickle cell retinopathy after the occurrence of gestational diabetes and pregnancy-induced hypertension